Pharmaceutical Research

, Volume 24, Issue 9, pp 1618–1627

Enhanced Intercellular Retention Activity of Novel pH-sensitive Polymeric Micelles in Wild and Multidrug Resistant MCF-7 Cells


  • Ghazal Mohajer
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
  • Eun Seong Lee
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
Research Paper

DOI: 10.1007/s11095-007-9277-5

Cite this article as:
Mohajer, G., Lee, E.S. & Bae, Y.H. Pharm Res (2007) 24: 1618. doi:10.1007/s11095-007-9277-5



The purpose of this work was to demonstrate the advantage of using pH-sensitive polymeric mixed micelles (PHSM) composed of poly(l-histidine) (polyHis)/poly(ethylene glycol) (PEG) and poly(l-lactic acid) (pLLA)/PEG block copolymers with folate conjugation to increase drug retention in wild-type and MDR tumor cells.

Materials and Methods

Both wild-type and multidrug resistant (MDR) human breast adenocarcinoma (MCF-7) cell lines were used to investigate the accumulation and elimination of doxorubicin (DOX), PHSM with folate (PHSM/f), and pH-insensitive micelles composed of pLLA/PEG block copolymer with folate (PHIM/f).


Cells treated with PHSM/f showed decelerated elimination kinetics compared to cells treated with PHIM/f. MDR cells treated with drug-containing PHSM/f for 30 min retained 80% of doxorubicin (DOX) even after incubation for 24 h in the absence of drug. On the other hand, cells treated with drug-containing PHIM/f retained only 40% of DOX within the same period of time. Flow cytometry and confocal microscopy confirmed these results.


Cellular entry of the micelles occurred via receptor-mediated endocytosis using folate receptors. The pH-induced destabilization of PHSM/f led to rapid distribution of drug and polymer throughout the cells, most likely due to polyHis-mediated endosomal disruption. This reduced the likelihood of drug efflux via exocytosis from resistant tumor cells.

Key words

exocytosisfolatemultidrug resistancepH-sensitive polymeric micellepoly(l-histidine)

Copyright information

© Springer Science+Business Media, LLC 2007